2-,3-,5-, and/or 8-substituted dibenzoxazepine compounds, pharmaceutical compositions and methods for treating pain

ABSTRACT

The present invention provides substituted dibenzoxazepine compounds of Formula I: ##STR1## which are useful as analgesic agents for the treatment of pain, pharmaceutical compositions comprising a therapeutically-effective amount of a compound of Formula I in combination with a pharmaceutically-acceptable carrier, and a method for eliminating or ameliorating pain in an animal comprising administering a therapeutically-effective amount of a compound of Formula I to the animal.

This application is a National Application under 35 USC §371 of pendingInternational Application No. PCT/US92/08103, filed on Sep. 28, 1992,which is a continuation-in-part application of application U.S. Ser. No.07/788,074, filed on Nov. 5, 1991, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention generally relates to compounds havingpharmacological activity which are useful as pharmacological agents and,more particularly, as analgesic agents for the treatment of pain, topharmaceutical compositions containing one or more of these compounds,and to methods of treatment employing these compounds. Moreparticularly, the present invention concerns substituted dibenzoxazepinecompounds, pharmaceutical compositions containing one or more of thesecompounds in combination with a pharmaceutically-acceptable carrier, andmethods of treating pain employing these compounds.

Analgesic compounds are agents which alleviate pain without causing aloss of consciousness and, thus, which are useful for treating pain and,often, for reducing inflammation.

The major classes of analgesic compounds include narcotic analgesics, oropiates, compounds which alleviate pain and induce sleep, andanalgesic-antipyretic compounds, compounds which alleviate pain andreduce fever, such as salicylates.

Although the efficacy of opiates in relieving pain is well established,the associated addiction liability of opiates is a distinct disadvantageof these compounds.

While salicylate and salicylate-like agents (nonsteroidalantiinflammatory agents or NSAIDS) are also efficacious in relievingpain, they often exhibit undesirable side effects, such asgastrointestinal irritation, as with aspirin, allergic response, as withaspirin, and/or liver toxicity with extended use, as with acetaminophen.

The compounds of the present invention are neither opiates norsalicylates, and represent another class of compounds which are usefulas analgesic agents.

2. Description of the Related Art

U.S. Pat. Nos. 4,559,336 and 4,614,617 (a continuation-in-part of U.S.Pat. No. 4,559,336) disclose8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(sulfinyl-and sulfonyl-containing acyl)hydrazides, and intermediates thereof.

U.S. Pat. No. 3,534,019 discloses hydrazides of dibenzoxazepine-,dibenzothiazepine- and dibenzodiazepine-carboxylic acids.

U.S. Pat. No. 3,624,104 discloses aralkanoyl derivatives ofdibenzoxazepine-N-carboxylic acid hydrazide compounds.

U.S. Pat. No. 3,989,719 discloses N,N'-diacyl hydrazines.

U.S. Pat. Nos. 3,917,649 and 3,992,375 (a divisional of U.S. Pat. No .3,917,649) disclose dibenzoxazepine N-carboxylic acid hydrazinecompounds.

U.S. Pat. Nos. 4,045,442, 4,125,532 (a divisional of U.S. Pat. No.4,045,442 ) and 4,170,593 (a divisional of U.S. Pat. No. 4,125,532)disclose 1-(substitutedamino)alkanoyl-2-(dibenzoxazepine-10-carbonyl)hydrazine compounds.

U.S. Pat. No. 4,559,337 discloses8-chlorodibenz-[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-(alkoxy-containing acyl)hydrazide compounds.

GB 1 522 003 discloses1-acyl-2-(8-chloro-10,11-dihydrodibenz[b,f][1,41oxazepine-10-carbonyl)hydrazinecompounds.

GB 1 331 892 discloses derivatives of dibenzoxazepine N-carboxylic acidhydrazides.

European Patent Application Publication No. 0 193 822 discloses8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, 2-(thio-,sulfinyl- and sulfonyl-containing acyl)hydrazide compounds.

European Patent Application Publication No. 0 218 077 discloses8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid,2-[(substituted phenylsulfinyl)alkanoyl]hydrazide compounds and8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[(substituted phenylsulfonyl)alkanoyl]hydrazide compounds, andintermediates used in the preparation of these compounds.

European Patent Application Publication No. 0 012 385 disclosesdibenz[b,f][1,4]oxazepine-derivatives.

German Patent Application Publication No. 1,170,322 discloses10-substituted-dibenz[b,f][1,4]oxazepin-11(10H)-ones.

Netherlands Patent No. 67,00603 discloses substituteddibenz[b,f][1,4]oxazepine-11(10H)-one compounds.

Drower et al., "The Antiociceptive Effects of Prostaglandin Antagonistsin the Rat," European Journal of Pharmacology, 133, 249-256 (1987),disclose the study of the antinociceptive properties of two competitiveantagonists of prostaglandins of the E series,8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid,2-acetylhydrazide and8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid,2-(5-chloro-1-oxopentyl)hydrazide.

J. H. Sanner, "Dibenzoxazepine Hydrazides as Prostaglandin Antagonists,"Intra-Science Chem. Rept., 6(1), 1-9 (1972), describes experimentsperformed with two dibenzoxazepine derivatives designated SC-18637 andSC-19220, and shown below, and found that SC-18637 and SC-19220 inhibitthe stimulant actions of prostaglandins on isolated smooth musclepreparations. ##STR2##

K. Nagarajan et al., "Synthesis of10,11-Dihydrodibenz[b,f][1,4]oxazepine Derivatives as PotentialAnticonvulsants & Psychotropic Agents," Indian Journal of Chemistry,24B, 840-844 (1985), disclose the synthesis of acyl, carbamoyl andthiocarbamoyl derivatives of 10,11-dihydrodibenz[b,f][1,4]oxazepine,most of which have either a nitro or an amino group at position-2, asanalogues of carbamazepine, and the evaluation of these derivatives asanticonvulsants associated with neuroleptic activity.

Other art which relates to the present invention includes that which isdiscussed below.

D. E. MacIntyre et al., "Antagonism of Human Platelet Responses toStimulatory and Inhibitory Prostaglandins," Prog Lipid. Res., 20(1-4),453-9 (1981), disclose on Page 454, Lines 11-12, Page 458, Lines 43-44,and in Table 1, two dibenzoxazepine compounds designated SC-19220 andSC-25191, and shown above and below, respectively, which were employedin an investigation of the effects of prostaglandin antagonists onplatelet responses to stimulatory and inhibitory prostaglandins.##STR3##

R. Gimet et al., "Quantitative Determination of Polymorphic Forms in aFormulation Matrix Using the Near Infra-Red Reflectance AnalysisTechnique," J. Pharmaceutical & Biomedical Analysis, 5(3), 205-211(1987), disclose an analytical method for the determination of thepolymorphic transformation of an active ingredient in a solid dosageform matrix, and discuss a compound designated SC-25469, and shownbelow, at Page 206, Lines 16-23. ##STR4##

J. H. Sanner et al., "Structure-Activity Relationships of someDibenzoxazepine Derivatives as Prostaglandin Antagonists," Advances inthe Biosciences, 9, 139-148 (1972), disclose tests for prostaglandinantagonism on isolated guinea-pig ileum and rat stomach fundus stripswith the n-butanoyl, i-butanoyl and n-hexanoyl analogs of SC-19220 and,on Page 140, Lines 11-18, show the chemical structures of the compoundsused in the study.

A. Rakovska et al., "Antagonistic Effect of SC-19220 on the Responses ofGuinea-Pig Gastric Muscles to Prostaglandins E₁, E₂ and F₂," Arch. int.Pharmacodyn, 268, 59-69 (1984), disclose a study of the contractileresponses of guinea-pig gastric muscles to SC-19220, and theprostaglandin-blocking activity and specificity of SC-19220 on thesemuscles.

W. E. Coyne et al., "Anticonvulsant Semicarbazides," J. Med. Chem.,11(6), 1158-1160 (1968), disclose the investigation of thestructure-activity relationship of the anticonvulsant activity of aseries of semicarbazides which was synthesized from various tricyclicamines (see Table I, Page 1160).

K. Gyires et al., "The Use of the Writhing Test in Mice for ScreeningDifferent Types of Analgesics, Arch. int. Pharmacodyn, 267, 131-140(1984), describe a comparison of the analgesic potency of someprostaglandin synthesis inhibitors, including SC-19220, and morphineusing the writhing test. SC-19220 is discussed on Page 133, Lines 10 and14-16, in Table II (Page 134), and on Page 135, Lines 16-25, and Page137, Lines 34-38.

A. Bennett et al., "Antagonism of Prostanoid-Induced Contractions of RatGastric Fundus Muscle by SC-19220, Sodium Meclofenamate, Indomethacin orTrimethoquinol," Br. J. Pharmac, 71, 169-175 (1980), disclose the studyof the effects of several compounds, including SC-19220, on contractionsof the rat stomach longitudinal muscle to several prostanoids. SC-19220is discussed on Page 175, Paragraph 1, Page 170, Paragraph 4, in Table 1and FIG. 2, on Page 172, Paragraph 2, and on Page 174, Paragraphs 1 and2.

C. A. Maggi et al., "The Effect of SC-19220, a Prostaglandin Antagonist,on the Micturition Reflex in Rats," European Journal of Pharmacology,152, 273-279 (1988), disclose a study in which SC-19220 is said to haveincreased the bladder capacity and reduced the voiding efficiency ofmicturition of urethane-anesthetized rats.

George et al., "Antagonism of Alcohol Hypnosis by Blockade ofProstaglandin Synthesis and Activity: Genotype and Time Course Effects,"Pharmacology Biochemistry & Behavior, 19, 131-136 (1983), disclose astudy of genetic and time-course factors of the effect of the antagonismof alcohol-induced behaviors of mice which have been pretreated withprostaglandin synthetase inhibitors and the effect of SC-19220 onethanol sleep time.

S. Nakayo et al., "Inhibitory Effect of Bassianolide, ACyclodepsipeptide, on Drug-Induced Contractions of Isolates SmoothMuscle Preparations," Japan. J. Pharmacol., 32, 55-64 (1982), disclose astudy of the effect of bassianolide on the contractile responses inducedby various types of neurotransmitters and autacoids. SC-19220 wasemployed in this study, and is discussed on Page 57, Paragraph 1, inFIGS. 2 and 3, in Table 1, and on Page 60, Paragraph 1, Page 62,Paragraph 3, and Page 63, Paragraph 2.

A. Gomes et al., "Pharmacodynamics of Venom of the Centipede Scolopendrasubspinipes dehaani, "Indian Journal of Experimental Biology, 20,615-618 (1982), disclose an investigation of the pharmacodynamic actionsof the venom of the tropical centipede S. subspinipes. SC-19220 wasemployed in this study and is discussed on Page 615 (abstract), Page616, Line 30, Page 617, Lines 13-18, in FIGS. 4 and 5, and on Page 618,Lines 23-26.

Each of the documents described hereinabove discloses compounds whichare structurally different from the compounds of the present invention.Thus, the compounds of the present invention are structurally distinctfrom that which has been described in the art.

Compounds of the present invention have been found to exhibit activityas prostaglandin E₂ antagonists. Some of these compounds weresurprisingly and unexpectedly found to be equipotent as prostaglandin E₂antagonists compared to prostaglandin antagonists reported in theliterature, which are structurally different from the compounds of thepresent invention.

Moreover, compounds within the present invention, such as the compoundshown and described in Example 8 hereinbelow, were found to be highlywater soluble. Thus, these compounds may be much more easily formulatedinto compositions which are suitable for oral, parenteral and othermodes of administration than compounds which are not water soluble.

SUMMARY OF THE INVENTION

The present invention provides compounds having a structure of FormulaI: ##STR5## or a pharmaceutically-acceptable salt, ester or amidethereof, wherein:

R¹ is hydrogen, halogen, hydroxy or ##STR6##

R² is hydrogen, halogen or, trifluoromethyl;

R³ is hydrogen or alkyl;

W is --CH═CH--, --(CH₂)₂ -- or --C.tbd.C--;

X is oxygen or --NH--;

n is an integer of from 0 to 5;

Z is oxygen, sulfur, ##STR7##

Y is hydrogen, alkyl, hydroxy, alkoxy, aryl, heteroaryl, ##STR8## withthe proviso that Y is not hydroxy, alkoxy, ##STR9## when n is 0.

The present invention also provides pharmaceutical compositions whichare pharmaceutically acceptable, and which comprise atherapeutically-effective amount of a compound of Formula I incombination with a pharmaceutically-acceptable carrier, and a method foreliminating or ameliorating pain in an animal comprising administering atherapeutically-effective amount of a compound of Formula I to theanimal.

DETAILED DESCRIPTION OF THE INVENTION

(1) Definitions

For purposes of clarity, the terms and phrases used throughout thisspecification and the appended claims are defined in the manner setforth directly below.

Some of the chemical structures which are presented in thisspecification and the appended claims have been drawn using theconvention which employs lines to represent alkyl radicals, which isknown by those of skill in the art.

The term "alkyl" as used herein means a saturated hydrocarbon radicalhaving from one to ten carbon atoms, and within which includes from oneto five carbon atoms, and further within which includes from one tothree carbon atoms, which can be a straight or branched chain.Representative of such radicals are methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, isobutyl, tert-butyl, pentyl and the like.

The term "alkoxy" as used herein means an alkyl radical, as definedabove, having one or more hydrogen atoms replaced by an oxygen atom.Representative alkoxy groups include methoxy, ethoxy, propoxy,tert-butoxy and the like.

The term "aryl" as used herein means unsubstituted 5- and 6-memberedsingle-ring aromatic radicals, for example, phenyl.

The term "analgesia" as used herein means the reduction, or absence, ofsensibility to pain, designating particularly the relief of pain withoutloss of consciousness.

The term "animal" as used herein includes mammals and nonmammals, andfurther includes humans and nonhuman mammals.

The abbreviation "Bu" as used herein means butyl (--CH₂ CH₂ CH₂ CH₃).

The term "acyloxy" as used herein means ##STR10##

The term "composition" as used herein means a product which results fromthe combining of more than one ingredient.

The abbreviation "DMF" as used herein means dimethylformamide.

The abbreviation "DSC" as used herein means Differential ScanningCalorimetry.

The phrase "EC₅₀ " dose as used herein means that dose of a compound ordrug which produces a 50% inhibition in a biological effect, such ascontractions in isolated segments of guinea pig ileum.

The phrase "ED₅₀ dose" as used herein means that dose of a compound ordrug which produced a biological effect, such as producing analgesia, in50% of the animals to which the compound or drug was administered.

The abbreviation "Et" as used herein means ethyl (--CH₂ CH₃).

The abbreviation "EtOH" as used herein means ethanol (CH₃ CH₂ OH).

The abbreviation "Et₃ N" as used herein means triethylamine.

The abbreviation "EtOAc" as used herein means ethyl acetate.

The term "halogen" as used herein means chlorine (Cl), bromine (Br),fluorine (F) and/or iodine (I).

The term "heteroaryl" as used herein means an aryl radical, as definedabove, including from one to four heteroatoms, as defined below.Representative heteroaryls include thienyl, furanyl, pyridinyl,imidazolyl, pyrimidyl, (is)oxazolyl, thiazolyl, triazolyl, tetrazolyl,pyrrolyl and the like.

The term "heteroatom" as used herein means an atom of any element otherthan carbon or hydrogen.

The term "hydroxy" as used herein means the group --OH.

The abbreviation "HOAc" as used herein means acetic acid.

The term "intragastrically" and/or the abbreviation "i.g." as usedherein means that a compound or drug was administered into the stomach.

The abbreviation "Me" as used herein means methyl (--CH₃).

The abbreviation "MeOH" as used herein means methanol (CH₃ OH).

The abbreviation "MPLC" as used herein means Medium Pressure LiquidChromatography.

The abbreviation "n-BuOH" as used herein means n-butanol (CH₃ CH₂ CH₂CH₂ OH).

The phrases "parenteral administration" and "administered parenterally"as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrase "pharmaceutically acceptable" is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically-acceptable carrier" as used herein means apharmaceutically-acceptable material, composition or vehicle, as defineddirectly above, such as a liquid or solid filler, diluent, excipient,solvent or encapsulating material, involved in carrying or transportinga chemical compound or pharmaceutical agent from one organ, or portionof the body, to another organ, or portion of the body. Some examples ofmaterials which can serve as pharmaceutically-acceptable carriersinclude: (1) sugars, such as lactose, glucose and sucrose; (2) starches,such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) excipients, such as cocoa butter and suppository waxes; (9)oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; (10) glycols, such as propyleneglycol; (11) polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; (12) esters, such as ethyl oleate and ethyllaurate; (13) agar; (14) buffering agents, such as magnesium hydroxideand aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17)isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20)phosphate buffer solutions; and (21) other non-toxic compatiblesubstances employed in pharmaceutical formulations.

The phrase "pharmaceutically-acceptable salts" as used herein refers tonon-toxic salts of the compounds of the present invention which aregenerally prepared by reacting the free base with a suitable organic orinorganic acid, or which are prepared by reacting the free acid with asuitable base. Representative salts include the hydrochloride,hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, palmitate,stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate,maleate, fumarate, succinate, tartrate, napsylate, clavulanate and thelike salts and alkali metal salts such as sodium and potassium andalkaline earth salts, such as calcium and magnesium.

The term "phenyl, "and the abbreviation "Ph", as used herein means thegroup C₆ H₅ --, derived from benzene.

The phrase "protecting group" as used herein means substituents whichprotect the reactive functional group from undesirable chemicalreactions. Examples of such protecting groups include esters ofcarboxylic acids, ethers of alcohols and acetals and ketals of aldehydesand ketones.

The phrase "N-protecting group" or "N-protected" as used herein meansthose groups intended to protect the N-terminus of an amino acid orpeptide, to protect an amino group against undesirable reactions duringsynthetic procedures and includes, but is not limited to, sulfonyl,acyl, acetyl, pivaloyl, t-butyloxycarbonyl (Boc), carbonylbenzyloxy(Cbz), benzoyl and an L- or D-aminoacyl residue, which may itself beN-protected similarly.

The abbreviation "s.c." as used herein means that a compound or drug wasadministered subcutaneously.

The phrase "therapeutically-effective amount" as used herein means anamount of a compound, material, composition which is an effective dosefor eliminating or ameliorating pain in an animal, or for producing someother desired therapeutic effect, at a reasonable benefit/risk ratioapplicable to any medical treatment.

The abbreviation "THF" as used herein means tetrahydrofuran.

The phrases "title compound" and "title product" as used herein meanthat compound or product whose chemical name is given, and/or whosestructure is shown, in the particular example referred to. If noparticular example is referred to, it means that compound or productwhose chemical name is given, and/or whose structure is shown, in theparticular example in which it appears.

(2) Description of Invention

In one aspect, the present invention provides compounds comprising astructure of Formula I, as described above, andpharmaceutically-acceptable salts, esters and amides thereof.

The compounds of the present invention comprise a class of substituteddibenzoxazepine compounds in which the 2-, 3-, 5- and/or 8-position,and/or the side chain, is substituted. Such compounds have been shown toexhibit activity as prostaglandin E₂ antagonists.

Specific compounds within the scope of the invention include, but arenot limited to, the compounds discussed in the examples presented below,as well as the pharmaceutically-acceptable salts, esters and amidesthereof.

Contemplated equivalents of the compounds described in Formula I includecompounds which otherwise correspond thereto, and which have the samegeneral properties thereof, wherein one or more simple variations ofsubstituents are made which do not adversely affect the efficacy of thecompound.

Certain compounds of this invention may exist in geometric orstereoisomeric forms. See, for example, the compounds shown anddescribed in Examples 3 and 4 hereinbelow. The present inventioncontemplates all such compounds, including cis- and trans-geometricisomers, R- and S-enantiomers, diastereomers, d-isomers, l-isomers, theracemic mixtures thereof, and other mixtures thereof, as falling withinthe scope of the invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in this invention.

Certain compounds of the present invention may contain a basicfunctional group, such as amino or alkylamino, and are, thus, capable offorming pharmaceutically-acceptable salts withpharmaceutically-acceptable acids. The term "pharmaceutically-acceptablesalts" in this respect, refers to the relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ during the final isolation andpurification of the compounds of the invention, or by separatelyreacting a purified compound of the invention in its free base form witha suitable organic or inorganic acid, and isolating the salt thusformed. Representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate,palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts and the like.(See, for example, S. M. Berge et al., "Pharmaceutical Salts," J PharmSci., 66:1-19 (1977).)

In other cases, the compounds of the invention may contain one or moreacidic functional groups and, thus, are capable of formingpharmaceutically-acceptable salts with pharmaceutically-acceptablebases. The term "pharmaceutically-acceptable salts" in these instancesrefers to the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present invention. These salts can likewise beprepared in situ during the final isolation and purification of thecompounds, or by separately reacting the purified compound in its freeacid form with a suitable base, such as the hydroxide, carbonate orbicarbonate of a pharmaceutically-acceptable metal cation, with ammonia,or with a pharmaceutically-acceptable organic primary, secondary ortertiary amine. Representative alkali or alkaline earth salts includethe lithium, sodium, potassium, calcium, magnesium, and aluminum saltsand the like. Representative organic amines useful for the formation ofbase addition salts include ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine and the like. (See, forexample, S. M. Berge et al., "Pharmaceutical Salts," supra.)

In another aspect, the present invention providespharmaceutically-acceptable compositions which comprise atherapeutically-effective amount of one or more of the compounds ofFormula I, as described hereinabove, formulated together with one ormore pharmaceutically-acceptable carriers. The pharmaceuticalcompositions of the invention may be specially formulated for oraladministration in solid or liquid form, for parenteral injection, or forrectal or vaginal administration.

In yet a further aspect, the present invention provides a method foreliminating or ameliorating pain in an animal, and methods for treatingcentral nervous disorders, including convulsions and ischemia, as wellas asthma, enuresis, arrhythmia, diarrhea, dysmenorrhea, osteoporosis,urinary incontinence, gastric hypermotility and irritable bowel syndromein an animal, comprising administering a therapeutically-effectiveamount of a compound of Formula I, as described hereinabove, to theanimal.

The most preferred embodiment of the present invention is the compounddescribed in Example 8 below.

(3) Utility

Compounds of the present invention exhibit activity as prostaglandin E₂antagonists (prostaglandin antagonists of the E₂ series).

Compounds within the present invention, and the pharmaceuticalcompositions comprising one or more of these compounds, are useful asanalgesic agents for the elimination or amelioration of pain in animals.

In addition to treating pain, these compounds and compositions would beuseful in treating convulsions, ischemia and other central nervoussystem disorders, as well as osteoporosis, dysmenorrhea, asthma,enuresis, arrhythmia, diarrhea, urinary incontinence, gastrichypermotility and irritable bowel syndrome by virtue of their activityas prostaglandin E₂ antagonists. They would also be useful asantipyretic agents by virtue of this activity.

(4) Methods of Preparation

In general, the compounds of the present invention may be prepared bythe methods illustrated in the following general reaction schemes, or bymodifications thereof, using readily-available starting materials,reagents and conventional synthesis procedures. Unless otherwisespecified, the various substituents of the compounds and materialspresent in the general reaction schemes are defined in the same manneras they are defined above in Formula I.

If a particular enantiomer of a compound of the present invention isdesired, it may be prepared by chiral synthesis, or by derivation with achiral auxiliary, where the resulting diastereomeric mixture isseparated and the auxiliary group cleaved to provide the pure desiredenantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

In each of the general reactions schemes, Z may be oxygen, sulfur,--SO-- or --SO₂ --. Where Z is sulfur, oxidation of the sulfur may beachieved with hydrogen peroxide to have Z become --SO--. Oxidation ofthe --SO-- group may then be achieved with hydrogen peroxide to have Zbecome --SO₂ --. This is illustrated in General Reaction Scheme No. 1.

In each of the general reaction schemes, W may be --CH═CH--, --(CH₂)₂ --or --C.tbd.C-- and X may be oxygen or --NH--. ##STR11##

With respect to General Reaction Scheme No. 1, an appropriateheterocycle, such as dibenzoxazepine (where Z is oxygen), mono- ordisubstituted with R¹ and/or R² wherein R¹ is hydrogen, halogen, oracyloxy and R² is hydrogen, halogen, or trifluoromethyl, is reacted withmaleic anhydride in the presence of triethylamine.

To yield the saturated or cis esters or amides, the resulting acid fromabove is reacted with i-butyl chloroformate. To the resulting mixedanhydride is added alcohols and amines of general structures, Y(CH₂)_(n)OH or Y(CH₂)_(n) NH₂ wherein Y can be hydrogen, alkyl, alkoxy, aryl,heteroaryl, amino suitably protected, hydroxy suitably protected,methylamino suitably protected or dimethylamino. If product wherein R¹is hydroxy is desired, the product is obtained by reacting the acyloxylintermediate with Na₂ CO₃. If product wherein Y is hydroxy, amino, ormonomethylamino is desired, the intermediate, wherein Y is protectedamino or hydroxy, is reacted with Na₂ CO₃.

To yield the trans esters or amides, the resulting acid from above isreacted with oxalyl chloride. To the resulting acid chloride is addedalcohols and amines of general structures, Y(CH₂)_(n) OH or Y(CH₂)_(n)NH₂ wherein Y can be hydrogen, alkyl, alkoxy, aryl, heteroaryl, aminosuitably protected, hydroxy suitably protected, methylamino suitablyprotected or dimethylamino. If product wherein R¹ is hydroxy is desired,the product is obtained by reacting the acyloxyl intermediate with Na₂CO₃. If product wherein Y is hydroxy, amino, or monomethylamino isdesired, the intermediate, wherein Y is protected amino or hydroxy, isreacted with Na₂ CO₃. ##STR12##

With respect to General Reaction Scheme No. 2, an appropriateheterocycle, such as dibenzoxazepine (where Z is oxygen), mono- ordisubstituted with R¹ and/or R² wherein R¹ is hydrogen, halogen, oracyloxy and R² is hydrogen, halogen, or trifluoromethyl, is reacted withmonoesterified fumaric acid chloride wherein the ester group is of theform Y(CH₂)_(n) OH wherein Y can be hydrogen, alkyl, alkoxy, aryl,heteroaryl, amino suitably protected, hydroxy suitably protected,methylamino suitably protected or dimethylamino. If the product whereinR¹ is hydroxy is desired, the product is obtained by reacting theacyloxyl intermediate with Na₂ CO₃. If product wherein Y is hydroxy,amino, or monomethylamino is desired, the intermediate wherein Y isprotected amino or hydroxy, is reacted with Na₂ CO₃. ##STR13##

With respect to General Reaction Scheme No. 3, an appropriateheterocycle, such as dibenzoxazepine (where Z is oxygen), mono- ordisubstituted with R¹ and/or R² wherein R¹ is hydrogen, halogen, oracyloxy and R² is hydrogen, halogen, or trifluoromethyl, is reacted withphosgene in a suitable solvent such as toluene, to give thecorresponding carbamoyl chloride.

Propynoic acid is activated, for instance, by means of a mixed anhydridecoupling with isobutylchloroformate, and converted to the appropriateamide or ester, in which "X," "Y," and "n" have the same meaning , as inGeneral Reaction Scheme No. 1. This acetylenic amide or ester is thenreacted with the appropriate dibenzoxazepine carbamoyl chloride in thepresence of trans-benzyl(chloro)bis(triphenylphosphine)palladium(II) andcuprous iodide in refluxing triethylamine, to give the desired product.

The conditions for carrying out the individual steps in each of thegeneral reaction schemes presented above are conventional, well-known,and capable of wide variation.

Other methods known in the art can also be used to synthesize thecompounds of the present invention.

(5) Dosage and Mode of Administration

The compounds of the present invention, and the pharmaceuticalcompositions comprising one or more of these compounds in combinationwith a pharmaceutically-acceptable carrier, are useful in treating painin animals. A physician or veterinarian of ordinary skill in the art canreadily determine whether or not a particular patient is in pain.

The pharmaceutical compositions of the present invention, which willtypically comprise one or more of the compounds of Formula I as anactive ingredient in admixture with one or morepharmaceutically-acceptable carriers and, optionally, with one or moreother compounds, drugs or materials, are employed therapeutically and,thus, would generally be used under the guidance of a physician. Theappropriate dosage and form of administration of these compositions willbe suitably selected by methods which are consistent with conventionalpharmaceutical practices.

The pharmaceutical compositions of the present invention may bespecially formulated for oral administration in solid or liquid form,for parenteral injection, and/or for rectal or vaginal administration.They may be administered to humans and other animals for therapy by anysuitable route of administration, including orally, nasally, as by, forexample, a spray, rectally, intravaginally, parenterally,intracisternally and topically, as by powders, ointments or drops,including buccally and sublingually. While the preferred routes ofadministration are orally and parenterally, the most preferred mode ofadministration is orally.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the severity of the pain, theduration of the treatment, other drugs, compounds and/or materials usedin combination with the particular compound employed, the age, sex,weight, condition, general health and prior medical history of thepatient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required to alleviate or ameliorate a particular patient'spain. For example, the physician or veterinarian could start doses ofthe compound of the invention employed in the pharmaceutical compositionat levels lower than that required in order to achieve the desiredtherapeutic effect and gradually increase the dosage until the desiredeffect is achieved.

In general, a suitable daily dose of a compound of the present inventionwill be that amount of the compound which is the lowest dose effectiveto produce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, dosage levels in therange of from about 0.001 mg to about 10 g, more preferably from about 1mg to about 1000 mg, of active compound (a compound of Formula I) perkilogram of body weight per day are administered to a mammalian patient.However, the total daily usage of the compounds of Formula I, or thepharmaceutical compositions comprising such compounds, will bedetermined by an attending physician or veterinarian within the scope ofsound medical judgement.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical formulation (composition).

The pharmaceutical compositions of the present invention comprise acompound of the present invention together with one or morepharmaceutically-acceptable carriers thereof and, optionally, with othertherapeutic agents. Each carrier must be "acceptable" in the sense ofbeing compatible with the other ingredients of the formulation and notinjurious to the patient.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient (compoundof Formula I) which can be combined with a carrier material to produce asingle dosage form will vary depending upon the host being treated, theparticular mode of administration and all of the other factors describedabove. The amount of active ingredient which can be combined with acarrier material to produce a single dosage form will generally be thatamount of the compound which is the lowest dose effective to produce atherapeutic effect. Generally, out of one hundred per cent, this amountwill range from about 1 per cent to about ninety-nine percent of activeingredient, preferably from about 5 per cent to about 70 per cent, mostpreferably from about 10 per cent to about 30 per cent.

Methods for preparing these formulations or compositions include thestep of bringing into association a compound of the present inventionwith the carrier and, optionally, with one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound of the present inventionwith liquid carriers, or finely divided solid carriers, or both, andthen, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient (compound of Formula I) is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds; (7) wetting agents, such as, for example, cetylalcohol and glycerol monostearate; (8) absorbents, such as kaolin andbentonite clay; (9) lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and (10) coloring agents. In the case of capsules,tablets and pills, the pharmaceutical compositions may also comprisebuffering agents. Solid compositions of a similar type may also beemployed as fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugars, as well as high molecular weightpolyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved in sterile water, or some other sterile, injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically-acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient (compound of Formula I), the liquid dosage forms may containinert diluents commonly used in the art, such as, for example, water orother solvents, solubilizing agents and emulsifiers, such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils(in particular, cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonire, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the invention to the body. Such dosage formscan be made by dissolving, dispersing or otherwise incorporating acompound of the present invention in a proper medium, such as anelastomeric matrix material. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate of such fluxcan be controlled by either providing a rate-controlling membrane ordispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of drug to polymer, and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissue.

The injectable materials can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or in other sterile injectable mediumsjust prior to use.

The formulations may be presented in unit-dose or multi-dose sealedcontainers, for example, ampoules and vials, and may be stored in alyophilized condition requiring only the addition of the sterile liquidcarrier, for example water for injections, immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets of the type described above.

The pharmaceutical compositions of the present invention may also beused in the form of veterinary formulations, including those adapted forthe following: (1) oral administration, for example, drenches (aqueousor non-aqueous solutions or suspensions), tablets, boluses, powders,granules or pellets for admixture with feed stuffs, pastes forapplication to the tongue; (2) parenteral administration, for example,by subcutaneous, intramuscular or intravenous injection as, for example,a sterile solution or suspension or, when appropriate, by intramammaryinjection where a suspension or solution is introduced into the udder ofthe animal via its teat; (3) topical application, for example, as acream, ointment or spray applied to the skin; or (4) intravaginally, forexample, as a pessary, cream or foam.

While the various aspects of the present invention are described hereinwith some particularity, those of skill in the art will recognizenumerous modifications and variations which remain within the spirit ofthe invention. These modifications and variations are within the scopeof the invention as described and claimed herein.

(6) Examples

The following examples describe and illustrate the methods for thepreparation of the compounds of the present invention, as well as otheraspects of the present invention, and the results achieved thereby, infurther detail. Both anexplanation of, and the actual procedures for,the various aspects of the present invention are described whereappropriate. These examples are intended to be merely illustrative ofthe present invention, and not limiting thereof in either scope orspirit. Those of skill in the art will readily understand that knownvariations of the conditions and processes of the preparative proceduresdescribed in these examples can be used to prepare the compounds of thepresent invention, and the pharmaceutical compositions comprising suchcompounds.

In the examples, all parts are by weight unless otherwise indicated.

All starting materials and equipment employed in the examples arecommercially available. Sources for these materials include SigmaChemical Co. (St. Louis, Mo.), Aldrich Chemical Co. (Milwaukee, Wis.),Lancaster Synthesis (Windham, N.H.), Fisher Scientific (Pittsburgh,Pa.), Boehringer Mannheim Biochemicals (Indianapolis, Ind.), FlukaChemical Corp. (Ronkonkoma, N.Y.) and Chemical Dynamics Corp. (SouthPlainfield, N.J.). Most of the starting materials were obtained fromAldrich Chemical Co. (Milwaukee, Wis.).

All patents and publications referred to in the examples, and throughoutthe specification, are hereby incorporated herein by reference, withoutadmission that such is prior art.

Example 1 8 -chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine ##STR14##

The synthesis of the title compound is described in U.S. Pat. No.3,534,019, which is incorporated herein by reference.

Briefly, 200 parts of 2,5-dichloro-nitrobenzene were heated to 160° C.and stirred, and 160 parts of the potassium salt of salicylaldehyde wasadded over a period of 30 minutes. After the addition was complete, anexothermic reaction took place, and the temperature rose to about 195°C. Heating was discontinued until the reaction subsided, and the mixturewas heated for 1 hour at 150° C. The mixture was cooled, ice and waterwere added, and it was extracted with ether. The ether layer wasfiltered to remove insoluble material, and the resultant solution wasdried over sodium sulfate. The ether solvent was evaporated, and theresidual oil was recrystallized from a mixture of hexane and benzene togive 2-(2-nitro-4-chloro-phenoxy)benzaldehyde melting at about 100°-101°C.

A solution of 55 parts of the ether obtained in the preceding paragraphin 800 parts of ethanol was hydrogenated over Raney nickel catalyst atroom temperature and atmospheric pressure. When hydrogen uptake ceased,the catalyst was removed by filtration, and the ethanol solvent wasevaporated. The residue was dissolved in 500 parts by volume of hexane,filtered, and cooled. There was obtained yellowish-white crystals whichwere separated by filtration to give8-chloro-10,11-dihydrodibenz-[b,f][1,41oxazepine melting at about94°-95° C.

Example 24-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2Z-butenoicacid ##STR15##

A solution of the title compound of Example 1 (20.0 g, 86.6 mmol) andmaleic anhydride (25.5 g, 260 mmol) in CH₂ Cl₂ (1 L) and Et₃ N (50 mL)was stirred at room temperature for 72 hours under an N₂ atmosphere. Thesolvent was removed and the resulting residue was suspended in EtOAc(700 mL) and extracted with NaOH (1M, 3×300 mL). The extracts werecombined and the pH was brought to 3 with HCl (1M). The aqueous materialwas extracted with EtOAc. A precipitate formed at the interface, and wascollected by vacuum filtration to yield 7.5 g of a brown solid. TheEtOAc was evaporated to yield 7.5 g of a brown solid. The solids werecombined and dissolved in isopropyl ether/MeOH, refluxed and decolorizedwith carbon and filtered through celite. The solvent was evaporated toyield 7.5 g of a yellow solid. The product was then crystallized fromisopropyl ether to yield the title compound as a yellow solid (4.5 g).

DSC: 149° C.

Analysis for C₁₇ H₁₂ NO₄ Cl: Calculated: C: 61.92; H: 3.67; N: 4.25.Found: C: 61.65; H: 3.87; N: 4.31.

Example 3 Butyl 4-(8-chloro-10,1!-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2Z-butenoate ##STR16##

To a solution of the title compound of Example 2 (500 mg, 1.5 mmol) inCH₂ Cl₂ (10 mL) and N-methylmorpholine (0.2 mL, 1.7 mmol) at -60° C.under an Argon atmosphere was added isobutylchloroformate (0.2 mL, 1.55mmol). The reaction solution was stirred at -60° C. for 15 minutes andthen placed in a ice/MeOH bath (-15° C.) for 40 minutes, followed by theaddition of n-BuOH (0.3 mL). The reaction mixture was stirred at roomtemperature for 4 hours.

The reaction solution was poured onto EtOAc (200 mL), extracted with HCl(1M, 100 mL), NaOH (1M, 100 mL) and brine (saturated), dried (Na₂ SO₄)and evaporated to yield a brown oil. The material was thenchromatographed MPLC (silicagel, 3:2 Hexane:EtOAc) to yield the titlecompound (260 mg) as a colorless oil that crystallized on standing.

DSC: 92° C.

Analysis for C₂₁ H₂₀ NO₄ Cl: Calculated: C: 65.37; H: 5.22; N: 3.63.Found: C: 65.36; H: 5.39; N: 3.58.

Example 4 Butyl4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2E-butenoate##STR17##

To a solution of the title compound of Example 2 (200 mg, 0.64 mmol) inCH₂ Cl₂ (10 mL) and Et₃ N (0.2 mL) was added oxalyl chloride (0.2 mL,1.4 mmol). The solution was stirred at room temperature under a N₂atmosphere for 1 hour, followed by the addition of n-butanol (5 mL, 55mmol). The solvent was removed under reduced pressure, and the residuewas chromatographed (MPLC, silica gel, 85:15 hexane:EtOAc) to yield thetitle compound (140 mg) as a colorless oil.

Analysis for C₂₁ H₂₀ NO₄ Cl: Calculated: C: 65.37; H: 5.22; N: 3.63.Found: C: 65.36; H: 5.39; N: 3.58.

Example 5N-butyl-4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl-4-oxo-2Z-butenamide##STR18##

To a solution of the title compound of Example 2 (500 mg, 1.5 mmol) inCH₂ Cl₂ (10 mL) and N-methylmorpholine (0.2 mL, 1.7 mmol) at -60° C.under an Argon atmosphere was added isobutylchloroformate (0.2 mL, 1.55mmol). The reaction solution was stirred at -60° C. for 15 minutes andthen placed in an ice/MeOH bath (-15° C.) for 40 minutes, followed bythe addition of n-butylamine (0.22 mL, 2.25 mmol). The reaction mixturewas stirred at room temperature for 1 hour.

The reaction solution was poured onto CHCl₃ (200 mL), extracted with HCl(1M, 100 mL), NaOH (1M, 100 mL) and brine (saturated), dried (Na₂ S04)and evaporated to yield 500 mg of a yellow oil. The material was thencrystallized from ether/hexane to yield the title compound (250 mg) as awhite solid.

Analysis for C₂₁ H₂₁ N₂ O₃ Cl: Calculated: C: 65.54; H: 5.50; N: 7.28.Found: C: 64.95; H: 5.58; N: 7.10.

Example 64-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-4-oxo-N-(2-pyridinylmethyl)-2Z-butenamide##STR19##

To a solution of the title compound of Example 2 (500 mg, 1.5 mmol) inCH₂ Cl₂ (10 mL) and N-methylmorpholine (0.2 mL, 1.7 mmol) at -60° C.under an Argon atmosphere was added isobutylchloroformate (0.2 mL, 1.55mmol). The reaction solution was stirred at -60° C. for 15 minutes andthen placed in an ice/MeOH bath (-15° C.) for 40 minutes, followed bythe addition of 2-aminomethyl-pyridine (0.3 mL, 2.5 mmol). The reactionmixture was stirred at room temperature for 4 hours. The solvent wasremoved and the residue was chromatographed (MPLC, silica gel, 95:5CHCl₃ :MeOH) to yield the title compound (475 mg) as a yellow foam.

Analysis for C₂₃ H₁₈ N₃ O₃ Cl. 0.5 H₂ O: Calculated: C: 64.41; H: 4.47;N: 9.80. Found: C: 64.41; H: 4.47; N: 9.55.

Example 7 Methyl4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo -2E-butenoate##STR20##

To a stirring solution of monomethylmaleate (13 g, 100 mmol) in CH₂ Cl₂(150 mL) and Et₃ N (25 mL) was slowly added a solution of oxalylchloride(29 mL 750 mmol) in CH₂ Cl₂ (100 mL). The resulting brown solution wasstirred for 2 hours, and the solvent was removed under reduced pressureand the residue was dissolved in CH₂ Cl₂ (250 mL) and Et₃ N (25 mL). Asolution of the title compound of Example 1 (20 g, 100 mmol) in CH₂ Cl₂(125 mL) was added, and the resulting solution was stirred for 16 hours.

The solvent was removed and the residue was chromatographed on silicagel (CH₂ Cl₂) to yield 33 g of a brown gum. The gum was furtherchromatographed on silica gel (MPLC, 15:85 EtOAc:hexane) to yield thetitle compound (21 g).

DSC: 125° C.

Analysis for C₁₈ H₁₄ NO₄ Cl: Calculated: C: 62.89; H: 4.10; N: 4.07.Found: C: 62.79; H: 4.14; N: 4.08.

Example 8 4-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-N-[2-(dimethylamino)ethyl]-4-oxo-2E-butenamide, monohydrochloride##STR21##

To a solution of the title compound of Example 2 (1 g, 3.2 mmol) in CH₂Cl₂ (50 mL) and Et₃ N (1 mL) was added oxalyl chloride (1 mL, 7 mmol).The solution was stirred at room temperature under a N₂ atmosphere for 1hour. The solvent was removed under reduced pressure, and the residuewas redissolved in CH₂ Cl₂ (50 mL) and Et₃ N (0.5 mL), followed by theaddition of N,N-dimethyl-ethylenediamine (803 mg, 9.11 mmol). Thereaction mixture was stirred for 2 hours. The solvent was removed underreduced pressure, and the residue was dissolved in EtOAc (300 mL) andextracted with brine (saturated) and NaHCO₃ (saturated) dried (Na₂ SO₄)and evaporated to yield 771 mg of the free base. The free base was takenup in EtOH (10 mL) and added to HCl/EtOH (5 mL, 9.5M). The volume wasreduced to 10 mL. The product crystallized on standing at 10° C. toyield the title compound (450 mg).

DSC: 211° C.

Analysis for C₂₁ H₂₂ N₃ O₃ Cl×HCl×0.25 H₂ O: Calculated: C: 57.21; H:5.37; N: 9.53. Found: C: 57.03; H: 5.52; N: 9.54.

The title compound was determined to have a high water solubility (>80mg/mL) by methods known by those of skill in the art. In contrast,8-chlorodibenz[b,f][1,41oxazepine-10(11H)-carboxylic acid,2-[3(ethylsulfonyl)-1-oxopropyl]hydrazide, the synthesis of which isdescribed in Example 10 of U.S. Pat. No. 4,559,336, which isincorporated herein by reference, and whose structure is shown below,has a water solubility of 80 μg/mL. ##STR22##

Example 98-chloro-γ-oxo-N-(4-pyridinylmethyl)dibenz[b,f]-[1,4]oxazepine-10(11)-butanamide##STR23##

A mixture of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine (5 g),succinic anhydride (5 g), 4-dimethyl-aminopyridine (4 g) and1,2-dichloroethane (50 mL) was heated to reflux for 16 hours. Themixture was cooled to room temperature and shaken successively with 0.7N HCl, water, dried over MgSO₄ and concentrated. The residue waschromatographed over silica gel using a mixture of 1/1 ethyl acetate(EA)/hexane as eluant. Appropriate fractions were pooled andconcentrated in vacuo to leave 5.3 g of a thick gum [¹³ C NMR (CDCl₃) δ28.33, 28.69, 48.07]. To a stirred solution of this material (0.87 g) inCH₂ Cl₂ (5 mL) at -20° C. was added in succession 4-methylmorpholine(0.288 mL) and isobutyl chloroformate (0.34 mL). After 15 minutes,4-(aminomethyl)pyridine (0.268 mL) was added. The mixture was allowed towarm to room temperature over 16 hours. The mixture was concentrated invacuo. The residue was extracted with ethyl acetate and water. Theorganic phase was washed sequentially with saturated aqueous NaHCO₃ andwater, dried over MgSO₄ and concentrated in vacuo. The residue waschromatographed over silica gel using a mixture of 10/20/70/1methanol/ethyl acetate/heptane/triethylamine as eluant. Appropriatefractions were pooled and concentrated to give 0.82 g of the free baseof the title compound as a white solid. A solution of this material inCH₂ Cl₂ (3 mL) and 7N HCl in dioxane (3 mL) was concentrated in vacuo.The residue was taken up in water (15 mL) and lyophilized to give thetitle compound as a white solid. [¹³ C NMR (DMSO-d₆) δ 28.5, 29.8, 41.6,47.3].

Analysis calculated for C₂₃ H₂₀ ClN₃ O₃. 0.75 HCl. 0.75 H₂ O: C, 59.70;H, 4.85; N, 9.08; Cl, 13.41. Found: C, 59.80; H, 4.69; N, 9.03; Cl,13.52.

Example 10 8-chloro-N-[2-(dimethylamino)ethyl]-γ-oxodibenz[b,f][1,4]oxazepine-10(11)-butanamide ##STR24##

A mixture of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine (5 g),succinic anhydride (5 g), 4-dimethyl-aminopyridine (4 g) and1,2-dichloroethane (50 mL) was heated to reflux for 16 hours. Themixture was cooled to room temperature and shaken successively with 0.7NHCl, water, dried over MgSO₄ and concentrated. The residue waschromatographed over silica gel using a mixture of 1/1 ethyl acetate(EA)/hexane as eluant. Appropriate fractions were pooled andconcentrated in vacuo to leave 5.3 g of a thick gum [¹³ C NMR (CDCl₃) δ28.33, 28.69, 48.07]. To a stirred solution of this material (0.87 g) inCH₂ Cl₂ (5 mL) at -20° C. was added in succession 4-methylmorpholine(0.288 mL) and isobutyl chloroformate (0.34 mL). After 15 minutes,N,N-dimethylethylenediamine (0.29 mL) was added. The mixture was allowedto warm to room temperature over 16 hours. The mixture was concentratedin vacuo. The residue was extracted with ethyl acetate and water. Theorganic phase was washed sequentially with saturated aqueous NaHCO₃ andwater, dried over MgSO₄ and concentrated in vacuo. The residue waschromatographed over silica gel using a mixture of 10/20/70/1methanol/ethyl acetate/heptane/triethylamine as eluant. Appropriatefractions were pooled and concentrated to give 0.84 g of the free baseof the title compound as a white solid. A solution of this material inCH₂ Cl₂ (3 mL) and 7N HCl in dioxane (3 mL) was concentrated in vacuo.The residue was taken up in water (15 mL) and lyophilized to give thetitle compound as a white solid. [¹³ C NMR (DMSO-d₆) δ 28.5, 30.0, 33.8,42.2, 47.3, 55.7].

Analysis calculated for C₂₁ H₂₄ ClN₃ O₃. HCl: C, 57.54; H, 5.75; N,9.59; Cl, 16.18. Found: C, 57.21; H, 5.79; N, 9.50; Cl, 16.09.

Example 11 4-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-4-oxo-N-(4-pyridinylmethyl)-2E-butenamide ##STR25##

To a stirring solution of the title compound of Example 7 (1.0 g) in THF(30 mL) and H2O (15 mL) was added lithium hydroxide (210 mg). Theresulting solution was stirred for 2 hours. The solvent was removedunder reduced pressure and EtOAc (300 mL) and HCl (1M, 100 mL) wereadded to the residue. The EtOAc was separated, dried (Na₂ SO₄) andevaporated to yield 973 mg of a solid, which was used in the mannerdescribed in the next paragraph without further purification.

To a stirring solution of the product synthesized in the precedingparagraph (930 mg) and 4-aminomethyl pyridine (305 mg) in DMF (20 mL) at0° C. under a nitrogen atmosphere was added triethylamine (285 mg),1-hydroxybenzotriazole hydrate (381 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (541 mg).The reaction mixture was then stirred at ambient temperature for 18hours. The solvent was removed, and to the residue was added HCl (1M,200 mL), followed by extraction with EtOAc (3×200 mL). NaOH (1M, 200 mL)was added to the aqueous portion, which was extracted with EtOAc (3×200mL), dried (Na₂ SO₄) and evaporated to yield an oil. This oil wascrystallized from ether/hexane to yield the title compound (780 mg) as awhite solid.

DSC 238.7° C.

Analysis for C₂₃ H₁₈ N₃ O₃ Cl: Calculated C: 65.80; H: 4.32; N: 10.01;Cl: 8.44. Found: C: 65.51; H: 4.36; N: 10.05; Cl: 8.17.

Example 12 4-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-4-oxo-N-(4-pyridinylmethyl)-2E-butenamide, monohydrochloride ##STR26##

The free base of the title compound of Example 11 was dissolved in HCl(1M, 40 mL) and lyophilized. The product was then dissolved in glacialacetic acid (20 mL) and lyophilized to yield 638 mg of the hydrochloridesalt of the title Compound of Example 11.

Analysis for C₂₃ H₁₈ N₃ O₃ Cl×0.9 HCl×1 H₂ O: Calculated: C: 58.69; H:4.48; N: 8.93; Cl: 14.31. Found: C: 58.39; H: 4.14; N: 8.93; Cl: 13.94.

Example 13 4-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-4-oxo-N-(4-pyridinylmethyl)-2-butynamide, monohydrochloride ##STR27##

8-Chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carbonyl chloride issynthesized in the manner described in U.S. Pat. No. 3,534,019: Phosgene(13 g, 131.4 mmol) in toluene (45 g) is stirred for 2 hours at 5°-10° C.and then diethyl ether (70 g) is added. This is followed by the additionof a solution of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine (18.9g, 81.6 mmol), prepared in the manner described in Example 1, andtriethylamine (7.2 g, 9.92 mL, 71.2 mmol) in diethyl ether (140 g).After the addition is complete, the mixture is stirred for 2 hours, andthen is filtered. The solvent is then evaporated from the filtrate, andthe resulting residue is recrystallized from hexane, giving8-chlorodibenz[b,f][1,41oxazepine-10(11H)-carbonyl chloride.

A 1 L round bottom, three-necked flask is fitted with a magneticstirrer, N₂ inlet, stopper, and Y-tube which contains a thermometer anda drying tube outlet. Propiolic acid (5.0 g, 4.39 mL, 71.4 mmol) ischarged into the flask, as is methylene chloride (300 mL) andN,N-dimethylformamide (100 mL), and 5A molecular sieves (20 g). The N₂is turned on and the mixture is cooled to -40°. N-methylmorpholine (8.30g, 9.02 mL, 82.08 mmol) is added, and the mixture is stirred at a lowtemperature for 40 minutes. The temperature is lowered to -60°, andisobutylchloroformate (10.24 g, 9.81 mL, 74.97 mmol) is added all atonce. The mixture is warmed to -15° and stirred at that temperature for1 hour The mixture is then recooled to -60° and 4-(aminomethyl)pyridine(8.49 g, 7.97 mL, 78.52 mmol) is added all at once. The mixture isallowed to stir at room temperature overnight. The mixture is thenfiltered through a sintered glass funnel, and the residue is washed withmethylene chloride. The filtrate and washes are combined and washed withaqueous phosphate buffer at pH 7.5. The organic phase is dried (MgSO₄),filtered, and stripped to a solid, which is subjected to silica columnchromatography. The resulting N-[(4-pyridyl)methyl]propynamide is useddirectly in the next step.

8-Chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carbonyl chloride (2.0 g, 6.8mmol), N-[(4-pyridyl)methyl]propynamide (1.09 g, 6.8 mmol), cuprousiodide (0.10 g, 0.52 mmol),trans-benzyl(chloro)bis(triphenylphosphine)palladium(II) (0.10 g, 0.26mmol), and triethylamine (40 mL) are charged into a 100 mL flask, andrefluxed under argon for 16 hours. The mixture is stripped to a solid,and partitioned between methylene chloride and aqueous phosphate bufferpH 7.5. The organic phase is dried (MgSO₄), filtered, and stripped to asolid. The solid is subjected to silica column chromatography to yieldthe free base of the title compound.

The resulting free base is dissolved in diethyl ether. The solution istreated with 5 mL of 6N HCl/dioxane. The resulting precipitate iscollected by filtration and is dried to give the title compound.

The foregoing examples are provided to enable one of ordinary skill inthe art to practice the present invention. These examples are merelyillustrative, however, and should not be read as limiting the scope ofthe invention as it is claimed in the appended claims.

(7) Description of Assays

(a) Writhing Assay

The Writhing Assay is one of the most widely-used experimentalprocedures for measuring the analgesic activity of different narcoticand nonnarcotic analgesic agents, and involves the continuous,chemically-induced pain of visceral origin to an animal, such as a mouseor rat. [Gyires et al., Arch. int. Pharmacodyn, 267, 131-140 (1984); C.Vander Wende et al., Fed. Proc., 15, 494 (1956); Koster et al., Fed.Proc., 18, 412 (1959); and Witken et al., J. Pharmacol. exp. Ther., 133,400-408 (1961).]Chemicals which may be used to induce this pain includephenylbenzoquinone (PBQ) and acetic acid. As a result of the chemicalirritation to the animal, a characteristic stretching and writhing ofthe animal (dorsiflexion of the animal's back, extension of itshindlimbs and the strong contraction of its abdominal musculature) willgenerally occur. The intensity of this pain reaction is determined bythe number of writhes exhibited by the animal during a given period oftime. Drugs which reduce the number of writhes of the animal appear torestore the normal nociceptive threshold of the animal.

Compounds of the present invention exhibit analgesic activity in mice,as shown by the results of the Writhing Assay presented in Table Ihereinbelow.

Charles River male albino mice, weighing 20 to 30 grams, were used inthis assay.

Thirty minutes after subcutaneous or intragastric administration to tenmice of 30 mg per kilogram of body weight of a compound of the presentinvention ("test compound"), 0.1 mg per 10 g of body weight of a 0.025%w/v solution of PBQ was injected intraperitoneally into each mouse. Tenmice which were given saline in place of a test compound of theinvention were used as a control group.

Five minutes later, each mouse was individually placed into a glassbeaker for observation, and the number of writhes occurring during thefollowing ten-minute period was counted.

A test compound was considered to have produced analgesia in a mouse if,in accordance with the conditions set forth above, and under the testcriteria employed for this assay, after the administration of 30 mg perkilogram of body weight of a compound of the present invention to themouse, the number of writhes elicited by a mouse injected with PBQ wasequal to, or less than, one-half the median number of writhes recordedfor the saline-treated control group of mice that day, as described byTaber in "Predictive Value of Analgesic Assays in Mice and Rats,"Advances in Biochemical Psychopharmacology, 8, 191 (1974).

The results for the particular compounds of the present inventionanalyzed in this assay, and discussed in the examples identified belowwhich correspond thereto, are presented in Table I hereinbelow asfractions under the heading "WRITHING ASSAY." The fractions indicate thenumber of mice, out of ten, in which the test compound producedanalgesia.

The standard initial screening dose of a test compound employed in thisassay was 30 mpk per gram of body weight for both routes ofadministration. If this initial screening dose of the test compoundproduced analgesia in seven of ten mice, then the effect of additionaldoses of the test compound on the writhing response was evaluated, andthen the ED₅₀ dose was generally calculated. (The slopes of thedose-response curves for all test compounds analyzed were compared asdescribed by Tallarida and Murray, Manual of Pharmacologic Calculations,Page 11 (Springer Verlag, New York, 1981)).

All ED₅₀ doses calculated are also presented below as whole numbers inTable I under the heading "WRITHING ASSAY." As Table I shows, the mostpotent compound of the present invention tested in the Writhing Assaywas the compound shown and discussed in Example 8. Thus,4-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-N-[2-(dimethylamino)ethyl]-4-oxo-2E-butenamide,monohydrochloride (Example 8) was determined to be the most potentcompound of the invention tested in this assay and, thus, is the mostpreferred compound of the present invention.

(b) Prostaglandin (PGE) Antagonism Assay

In order to determine the effectiveness of several of the compounds ofthe present invention ("test compounds") as prostaglandin E₂antagonists, a prostaglandin antagonism assay was conducted, asdescribed below, to determine the ability of these compounds to inhibitprostaglandin E₂ -induced contractions of segments of guinea pig ileum.If a test compound inhibits prostaglandin E₂ -induced contractions, itsuggests that the compound functionally antagonizes prostaglandin E₂.

Male albino guinea pigs weighing 200 to 500 grams were sacrificed bycervical dislocation. The ilea were then quickly removed from the guineapigs and placed in a modified Tyrode solution, a solution which is knownto those skilled in the art, containing one-half of the usual amount ofmagnesium ions.

Segments of ileum about 2 cm long were then cut and mounted in a 10 mLtissue bath containing the modified Tyrode solution. The solution wasmaintained at 37° C. and aerated with a gaseous mixture of 95% oxygenand 5% carbon dioxide. Data for a control prostaglandin E₂ dose responsecurve plotting concentration of prostaglandin E₂ versus the intensity ofcontractions, detected isotonically, was then obtained by experimentallyadjusting the dose of the prostaglandin E₂ being injected into thetissue bath, in a manner known by those of skill in the art.

Solutions or suspensions containing an initial concentration (3micromolar) of a test compound in modified Tyrode solution ("testsolutions/suspensions") were then separately substituted for the controlbath solution. Each test solution/suspension was then kept in constantcontact with the ileum tissue, except for brief periods to drain thebath in preparation for rinsing with fresh test solution/suspension. Asecond prostaglandin E₂ dose response curve was then generated forprostaglandin E₂ in the, presence of a test compound.

A dose ratio of EC₅₀ doses was then calculated from the results of eachtest in a manner known by those of skill in the art. A test compound wasdetermined to be "active" if the initial concentration used yielded atleast a two-fold shift (dose ratio greater than or equal to 2) in thedose response curve for prostaglandin E₂. An estimated pA₂ value (astatistical constant which is a common measure of expressing the potencyof a particular drug as an antagonist) was reported for "active"compounds under the assumption that the slope of the Schild plot doesnot deviate significantly from -1.0. If the initial concentration oftest compound yielded at least a five-fold shift (dose ratio greaterthan or equal to 5) in the dose response curve for prostaglandin E₂,then varying concentrations of the test compound were assayed, and a PA₂value for that compound was calculated by Schild plot calculations, asdescribed by H. O. Schild, "pA, A New Scale for the Measurement of DrugAntagonism," Br. J. Pharmacol, 2, 189 (1947). The higher the valuecalculated for the PA₂, the more potent a particular compound is as aprostaglandin E₂ antagonist.

The results of this prostaglandin antagonism assay are also presented inTable I below. The compounds of the present invention which were testedin this assay, and for which results are presented in Table I,correspond to the particular examples specified in Table I.

                  TABLE I                                                         ______________________________________                                        Data Generated from the Assays                                                WRITHING ASSAY                                                                Number out of Nine or Ten                                                                           PGE                                                     or                    IN GUINEA PIG                                           Example                                                                              ED.sub.50 Dose (mpk)                                                                             ILEUM                                               Number S.C.        I.G.       pA.sub.2                                        ______________________________________                                        2      4/10        1/10       *                                               3      4/10        6/10       *                                               4      6/10        6/10       *                                               5      6/10        4/10       *                                               7      6/9         3/10       *                                               8      8.3         8.3        5.73                                            9      *           6/10       5.62                                            10     *           6/9        *                                               ______________________________________                                         * = Not Tested.                                                          

While the present invention has been described herein with somespecificity, and with reference to certain preferred embodimentsthereof, those of ordinary skill in the art will recognize numerousvariations, modifications and substitutions of that which has beendescribed which can be made, and which are within the scope and spiritof the invention. For example, effective dosages other than thepreferred ranges set forth hereinabove may be applicable as aconsequence of variations in the responsiveness of the animal beingtreated, dosage-related adverse effects, if any, and analogousconsiderations. Likewise, the specific pharmacological responsesobserved may vary according to, and depending upon, the particularactive compound selected, or whether there are present certainpharmaceutical carriers, as well as the type of formulation and mode ofadministration employed. Such expected variations and/or differences inthe results are contemplated in accordance with the objects andpractices of the present invention. It is intended therefore that all ofthese modifications and variations be within the scope of the presentinvention as described and claimed herein, and that the invention belimited only by the scope of the claims which follow, and that suchclaims be interpreted as broadly as is reasonable.

What is claimed is:
 1. A compound having a structure of the formula:##STR28## or a pharmaceutically-acceptable salt, ester or amide thereof,wherein: R¹ is hydrogen, halogen, hydroxy or ##STR29## R² is hydrogen,halogen or trifluoromethyl; R³ is hydrogen or alkyl;W is --CH═CH--,--(CH₂)₂ -- or --C.tbd.C--; X is oxygen or --NH--; n is an integer offrom 0 to 5; Z is oxygen, sulfur, ##STR30## Y is hydrogen, alkyl,hydroxy, alkoxy, aryl, heteroaryl, ##STR31## with the proviso that Y isnot hydroxy, alkoxy, ##STR32## when n is
 0. 2. A compound of claim 1wherein R¹ and R² are each independently hydrogen or halogen.
 3. Acompound of claim 2 wherein R¹ is hydrogen and R² is halogen.
 4. Acompound of claim 3 wherein R² is chlorine.
 5. A compound of claim 4wherein n is an integer of from 0 to
 3. 6. A compound of claim 5 whereinY is alkyl, hydroxy, alkoxy, aryl, heteroaryl, ##STR33##
 7. A compoundof claim 6 wherein Y is methyl, ethyl, propyl, hydroxy, methoxy, ethoxy,phenyl, thiophene furan pyridine or ##STR34## and Z is oxygen.
 8. Acompound of claim 7 wherein Y is methyl, ethyl, propyl, hydroxy,methoxy, pyridine or ##STR35##
 9. A compound of claim 8 wherein Y ismethyl, hydroxy, pyridine or ##STR36##
 10. A compound of claim 1,wherein the compound is: ##STR37##
 11. A compound of claim 1, whereinthe compound is: ##STR38##
 12. A compound of claim 1, wherein thecompound is: ##STR39##
 13. A compound of claim 1, wherein the compoundis: ##STR40##
 14. A compound of claim 1, wherein the compound is:##STR41##
 15. A compound of claim 1, wherein the compound is: ##STR42##16. A compound of claim 1, wherein the compound is: ##STR43##
 17. Acompound of claim 1, wherein the compound is: ##STR44##
 18. A compoundof claim 1, wherein the compound is: ##STR45##
 19. A compound of claim1, wherein the compound is: ##STR46##
 20. A compound of claim 1, whereinthe compound is: ##STR47##
 21. A compound of claim 1 wherein thecompoundis:4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2Z-butenoicacid; Butyl4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2Z-butenoate;Butyl4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2E-butenoate;N-butyl-4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2Z-butenamide;4-(8-chloro-10,11-dihydrodibenz [b,f]oxazepin10-yl)-4-oxo-N-(2-pyridinylmethyl)-2Z-butenamide; Methyl4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2E-butenoate;4-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-N-[2-(dimethylamino)ethyl]-4-oxo-2E-butenamide, monohydrochloride;8-chloro-γ-oxo-N-(4-pyridinylmethyl)dibenz[b,f][1,41oxazepine-10(11)-butanamide;8-chloro-N-oxo-N-[2-(dimethylamino)ethyl]-γ-oxodibenz[b,f][1,4]oxazepine-10(11)-butanamide;4-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-4-oxo-N-(4-pyridinylmethyl)-2E-butenamide;or4-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-4-oxo-N-(4-pyridinylmethyl)-2E-butenamide,monohydrochloride.
 22. A pharmaceutical composition comprising apharmaceutically-acceptable carrier and a therapeutically-effectiveamount of a compound of claim
 1. 23. The pharmaceutical composition ofclaim 22 wherein the compoundis:4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2Z-butenoicacid; Butyl4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2Z-butenoate;Butyl4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2E-butenoate;N-butyl-4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2Z-butenamide;Methyl4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2E-butenoate;4-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-N-[2-(dimethylamino)ethyl]-4-oxo-2E-butenamide, monohydrochloride;8-chloro-γ-oxo-N-(4-pyridinylmethyl)dibenz[b,f][1,41oxazepine-10(11)-butanamide;8-chloro-N-oxo-N-[2-(dimethylamino) ethyl]-γ-oxodibenz[b,f][1,4]oxazepine-10(11)-butanamide;4-(8-chloro-10,11-dihydrodibenz [b,f]oxazepin-10-yl)-4-oxo-N-(4-pyridinylmethyl)-2E-butenamide; or4-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-4-oxo-N-(4-pyridinylmethyl)-2E-butenamide,monohydrochloride.
 24. A method for treating pain in an animalcomprising administering to said animal a therapeutically-effectiveamount of a compound of claim
 1. 25. The method of claim 24 wherein thecompoundis:4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2Z-butenoicacid; Butyl4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2Z-butenoate;Butyl4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2E-butenoate;N-butyl-4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2Z-butenamide;Methyl4-(8-chloro-10,11-dihydrodibenz[b,f]-oxazepin-10-yl)-4-oxo-2E-butenoate;4-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-N-[2-(dimethylamino)ethyl]-4-oxo-2E-butenamide, monohydrochloride;8-chloro-γ-oxo-N-(4-pyridinylmethyl)dibenz[b,f][1,4]oxazepine-10(11)-butanamide;8-chloro-N-oxo-N-[2-(dimethylamino)ethyl]-γ-oxodibenz[b,f][1,4]oxazepine-10(11)-butanamide;4-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-4-oxo-N-(4-pyridinylmethyl)-2E-butenamide; or4-(8-chloro-10,11-dihydrodibenz[b,f]oxazepin-10-yl)-4-oxo-N-(4-pyridinylmethyl)-2E-butenamide,monohydrochloride.